Hepatocellular injury in hepatitis B virus (HBV) infection is believed to result from the immune-mediated mechanisms related to host clearance of this noncytopathic virus. The objective of this proposal is to examine genetic and molecular mechanisms of immune recognition of HBV antigens, and to characterize the antigen epitope to which the immune response is directed. Recent elucidation of higher molecular weight polypeptides present in the viral envelope has prompted studies focused on the immune response to these pre-S determinants. Specific studies will include: (1) the influence of H-2 and non-H-2-linked genes on the immune response to HBV antigens, including pre-S sequences and nucleocapsid antigens utilizing a series of H-2 congenic and intra-H-2 recombinant murine strains; (2) cellular correlates of in vivo antibody production including evaluation of functional T cell subsets, T cell-B cell interactions, and T and B cell precursor frequencies; (3) chemically synthesized peptide analogs of HBV antigens and proteolytic cleavage fragments will be used to study the nature of the antigenic epitopes recognized by T cell functional subsets and B cells; (4) examination of the mechanism of nonresponsiveness to HBV antigens and strategies to circumvent them; (5) analysis of the human humoral immune response to the recently described pre-S region determinants and, examination of the cellular localization of pre-S antigens by immunofluorescence and immunoelectron microscopy; and (6) application of this basic information towards strategies to design efficacious second generation recombinant and possibly synthetic HBV vaccines. This system has provided, and it is anticipated will continue to provide, critical information applicable to HBV vaccine development, understanding of pathogenetic mechanisms in HBV infection as well as basic information relating to immune recognition of complex protein antigens.